Compounds and compositions for treating solid tumors by intratumoral administration

Abstract

The invention provided herein includes pharmaceutical compositions comprising a TLR7 agonist having the structure of Formula (A), aluminum-containing particles, and one or more pharmaceutically acceptable excipient. The invention further provides the use of such compositions in the treatment of solid tumors either alone or in combination with one or more additional pharmaceutical compositions.

The invention claimed is: 
     
       1. A pharmaceutical combination, wherein the pharmaceutical combination is a non-fixed combination comprising:
 a) a first pharmaceutical composition comprising a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, aluminum-containing particles, a buffering agent and one or more pharmaceutically acceptable excipients: 
 
       
         
           
           
               
               
           
         
         
           wherein:
 R 1  is -L 1 R 4 , -L 1 R 5 , —OL 1 R 4 , —OL 1 R 5 , CH 3 , —C(═O)P(O)(OH) 2  or —C(═O)CF 2 P(O)(OH) 2 ; 
 R 2  is -L 2 R 4 , -L 2 R 6 , -L 2 L 3 L 2 R 6 , -L 2 L 3 R 4 , -L 2 L 3 L 2 R 4 , —OL 2 R 4 , —OR 4 , —OL 2 R 6 , —OL 2 L 3 R 6 , —OL 2 L 3 L 2 R 6 , —OL 2 L 3 R 4 , —OL 2 L 3 L 2 R 4  or —OCH 3 ; 
 each R 3  is independently selected from H and fluoro; 
 R 4  is —P(O)(OH) 2 , 
 R 5  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
 R 6  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
 L 1  is C 1 -C 6 alkylene, C 2 -C 6 alkenylene or —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene and C 2 -C 6 alkenylene of L 1  are substituted with 0 to 4 fluoro groups; 
 each L 2  is independently selected from C 1 -C 6 alkylene and —((CR 3 R 3 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 2  is substituted with 0 to 4 fluoro groups; 
 L 3  is arylene or a 5-6 membered heteroarylene; 
 each p is independently selected from 1, 2, 3, 4, 5 and 6, and 
 q is 1, 2, 3 or 4 
 
           and wherein
 one of the one or more pharmaceutically acceptable excipients is selected from mannitol and sucrose; 
 the composition has a pH in the range of 6.5 to 9.0, and 
 the aluminum-containing particles are a suspension of aluminum hydroxide particles; 
 
         
         b) a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor, 
         and 
         c) a third pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor, 
       
       wherein the checkpoint inhibitor of the third composition is different than the checkpoint inhibitor in the second composition. 
     
     
       2. A method for treating a solid tumor by administering to a subject in need thereof:
 a pharmaceutical combination comprising:
 i. a first pharmaceutical composition, 
 ii. a second pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor, and 
 iii. a third pharmaceutical composition comprising a checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor, 
 wherein:
 the checkpoint inhibitor of the third composition is different than the checkpoint inhibitor in the second composition; 
 the first pharmaceutical composition is administered intratumorally, and the second pharmaceutical composition and the third pharmaceutical composition are administered intratumorally, intramuscularly, intradermally, subcutaneously, intravenously, by intraperitoneal injection, by lavage or by infusion; 
 the pharmaceutical combination is a non-fixed combination, 
 and 
 the first pharmaceutical composition comprises a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof, aluminum-containing particles, a buffering agent and one or more pharmaceutically acceptable excipients: 
 
 
 
       
         
           
           
               
               
           
         
         
           
             
               wherein: 
                R 1  is -L 1 R 4 , -L 1 R 5 , —OL 1 R 4 , —OL 1 R 5 , CH 3 , —C(═O)P(O)(OH) 2  or —C(═O)CF 2 P(O)(OH) 2 ; 
                R 2  is -L 2 R 4 , -L 2 R 6 , -L 2 L 3 L 2 R 6 , -L 2 L 3 R 4 , -L 2 L 3 L 2 R 4 , —OL 2 R 4 , —OR 4 , —OL 2 R 6 , —OL 2 L 3 R 6 , —OL 2 L 3 L 2 R 6 , —OL 2 L 3 R 4 , —OL 2 L 3 L 2 R 4  or —OCH 3 ; 
                each R 3  is independently selected from H and fluoro; 
                R 4  is —P(O)(OH) 2 , 
                R 5  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
                R 6  is —CF 2 P(O)(OH) 2  or —C(O)OH; 
                L 1  is C 1 -C 6 alkylene, C 2 -C 6 alkenylene or —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene and C 2 -C 6 alkenylene of L 1  are substituted with 0 to 4 fluoro groups; 
                each L 2  is independently selected from C 1 -C 6 alkylene and —((CR 3 R 3 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 2  is substituted with 0 to 4 fluoro groups; 
                L 3  is arylene or a 5-6 membered heteroarylene; 
                each p is independently selected from 1, 2, 3, 4, 5 and 6, and 
                q is 1, 2, 3 or 4 
                and wherein: 
                one of the one or more pharmaceutically acceptable excipients is selected from mannitol and sucrose; 
                the composition has a pH in the range of 6.5 to 9.0, and 
                the aluminum-containing particles are a suspension of aluminum hydroxide particles. 
             
           
         
       
     
     
       3. The method of  claim 2 , wherein the solid tumor is head and neck squamous cell carcinoma (HNSCC), melanoma or a visceral tumor. 
     
     
       4. The method of  claim 2 , wherein the compound having the structure of Formula (A) is:
 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 (3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propyl)phosphonic acid; 
 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate; 
 ((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phosphonic acid; 
 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid; 
 (4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutyl)phosphonic acid; 
 (3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1,1-difluoropropyl)phosphonic acid; 
 3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonic acid; 
 2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonic acid; 
 (3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)phosphonic acid; 
 (2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethyl)phosphonic acid; 
 (6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexyl)phosphonic acid; 
 (6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexyl)phosphonic acid; 
 (4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzyl)phosphonic acid; 
 (2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethyl)phosphonic acid; 
 (5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentyl)phosphonic acid; 
 (4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)butyl)phosphonic acid, 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid; 
 (E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinyl)phosphonic acid; 
 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid; 
 (E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinyl)phosphonic acid, or 
 (5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonyl)phosphonic acid. 
 
     
     
       5. The method of  claim 2 , wherein the compound having the structure of Formula (A) is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. 
     
     
       6. The method of  claim 2 , wherein the first pharmaceutical composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and mannitol. 
     
     
       7. The method of  claim 2 , wherein the first pharmaceutical composition comprises 0.5 to 2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
       8. The method of  claim 2 , wherein the first pharmaceutical composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 5.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH of 7.5+/−0.3. 
     
     
       9. The method of  claim 2 , wherein the second pharmaceutical composition comprises a PD-1 receptor inhibitor. 
     
     
       10. The method of  claim 2 , wherein the second pharmaceutical composition comprises an anti-PD-1 antibody. 
     
     
       11. The pharmaceutical combination of  claim 1 , wherein the compound having the structure of Formula (A) is:
 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 3-(5-amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; 
 (3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propyl)phosphonic acid; 
 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate; 
 ((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phosphonic acid; 
 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid; 
 (4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutyl)phosphonic acid; 
 (3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1,1-difluoropropyl)phosphonic acid; 
 3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonic acid; 
 2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonic acid; 
 (3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)phosphonic acid; 
 (2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethyl)phosphonic acid; 
 (6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexyl)phosphonic acid; 
 (6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexyl)phosphonic acid; 
 (4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzyl)phosphonic acid; 
 (2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethyl)phosphonic acid; 
 (5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentyl)phosphonic acid; 
 (4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)butyl)phosphonic acid; 
 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid; 
 (E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinyl)phosphonic acid; 
 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid; 
 (E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinyl)phosphonic acid, or 
 (5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonyl)phosphonic acid. 
 
     
     
       12. The pharmaceutical combination of  claim 1 , wherein the compound having the structure of Formula (A) is 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid. 
     
     
       13. The pharmaceutical combination of  claim 1 , wherein the first pharmaceutical composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, a suspension of aluminum hydroxide particles, Tris buffer and mannitol. 
     
     
       14. The pharmaceutical combination of  claim 1 , wherein the first pharmaceutical composition comprises 0.5 to 2 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
       15. The pharmaceutical combination of  claim 3 , wherein the first pharmaceutical composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
       16. The pharmaceutical combination of  claim 1 , wherein the first pharmaceutical composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
       17. The pharmaceutical combination of  claim 1 , wherein the first pharmaceutical composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH in the range of 7.0 to 8.0. 
     
     
       18. The pharmaceutical combination of  claim 1 , wherein the first pharmaceutical composition comprises 1 mg/mL of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer, 5.5% (w/v) mannitol, and a suspension of aluminum hydroxide particles having an aluminum content of 2 mg/mL, and wherein the composition has a pH of 7.5+/−0.3. 
     
     
       19. The pharmaceutical combination of  claim 1 , wherein the first pharmaceutical composition comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxide particles, and wherein the (w/w) ratio of the weight of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid to the weight of aluminum in the suspension of particles is 1:20. 
     
     
       20. The pharmaceutical combination of  claim 1 , wherein the second pharmaceutical composition comprises a PD-1 receptor inhibitor. 
     
     
       21. The pharmaceutical combination of  claim 1 , wherein the second pharmaceutical composition comprises an anti-PD-1 antibody.